Anorectic toxicity of dihydroartemisinin, artemether, and arteether in rats following multiple intramuscular doses

During studies of arteether (AE), artemether (AM), and dihydroartemisinin (DQHS) neurotoxicity, the effect of 7 daily intramuscular doses (25, 50 and 100 mg/kg/d) of those antimalarial drugs on gastrointestinal function was investigated in rats. A modified Nichols' method was used to measure daily food and water consumption To estimate gastric transit, the total length amaranth (administered 40 minutes prior to sacrifice) dye traveled through small intestine were measured, and to determine gastric retention, the tied-off stomach pouch was removed and the contents weighed 24 hours after the last dose or when a rat became moribund or died. AM and AE dose solutions were prepared using sesame oil, whereas 50% dimethylacetamide (DMAC)/sesame oil was used for DQHS. The results showed that after dosing with 50 mg/kg for 7 days, 50% inhibition of food consumption (ID50) occurred at 1.9 days for DQHS, 3.9 days for AM, and 4.1 days for AE. Similar data were observed for water intake. After 100 mg/kg dosing, the ID(50)s for food and water consumption decreased to 2.8-2.9 days for AM and 3.1-3.7 days for AE. Food consumption and body weights were decreased following all three treatments, and rats exhibited neurologic symptoms at 25-100 mg/kg dose of DQHS and 50-100 mg/kg dose of AM and AE. In addition, the results constituted a 53% and 82% inhibition of gastric transit for AM and AE, respectively, at 25 mg/kg animals compared to control, and 100% inhibition was found in high doses (50 and 100 mg/kg) for all the three drugs. The gastric retention ratio (controls equal 1.0) was 26.0 for DQHS, 5.8 with AE, and 2.3 for AM rats following 50 mg/kg dosing. When the 100 mg/kg dose was administered, the gastric retention ratio doubled for AE (11.6) and AM (4.3). The consumption data indicated that DQHS was about 2-3 times more toxic to the anorexia than AM and AE at 25 and 50 mg/kg/day dose levels. Significant differences in gastric emptying and gastric transit activities between AE and AM were observed. Data demonstrated that after multiple intramuscular doses of DQHS, AM, or AE in rats food consumption and gastric emptying were decreased, gastric transit was inhibited, as reflected in a significant body weight reduction and death. Since an exhibition of the anorectic symptoms of AM and AE was at a lower dose than the neurologic signs in rats, the anorexia could be an early portent or prediction of the neurotoxicity in animals or humans.